Phosphodiesterases (PDEs) are a class of intracellular enzymes involved in the hydrolysis of the nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) to their respective nucleotide monophosphates. These cyclic nucleotides serve as secondary messengers in several cellular pathways, regulating an array of intracellular processes within neurons of the central nervous system including the activation of cAMP- and cGMP-dependent protein kinases that produce subsequent phosphorylation of proteins involved in regulation of synaptic transmission, synaptic plasticity, neuronal differentiation and survival.
So far, only a single gene for PDE2, PDE2A, has been identified; however, multiple alternatively spliced isoforms of PDE2A, which include PDE2A1, PDE2A2, and PDE2A3, have been reported. PDE2A was identified as a unique family based on primary amino acid sequence and distinct enzymatic activity. The human PDE2A3 sequence was isolated in 1997 (Rosman et al., Isolation and characterization of human cDNAs encoding a cGMP-stimulated 3′,5′-cyclic nucleotide phosphodiesterase, Gene, 191 (1):89-95, 1997).
Inhibition of PDE2A demonstrates enhanced cognitive function across multiple preclinical models of cognitive performance that reflect improvements in recognition memory, social interactions and working memory, which are all deficient in schizophrenia (Boess et al., Inhibition of phosphodiesterase 2 increases neuronal cGMP, synaptic plasticity and memory performance, Neuropharmacology, 47(7):1081-92, 2004). PDE2A inhibition also improved cognitive deficits that develop in aging and Alzheimer's disease (Domek-Lopacinska and Strosznajder, The effect of selective inhibition of cyclic GMP hydrolyzing phosphodiesterases 2 and 5 on learning and memory processes and nitric oxide synthetase activity in brain during aging, Brain Research, 1216:68-77, 2008). Bayer has published the biochemical and behavioral profile of BAY 60-7550, indicating a role in PDE2 inhibition in cognitive disorders (Brandon et al., Potential CNS Applications for Phosphodiesterase Enzyme Inhibitors, Annual Reports in Medicinal Chemistry 42: 4-5, 2007). However, this compound showed significant potency at other PDE isoforms and had high clearance and limited brain penetration and is not believed to be progressing in the clinic.
PDE2 inhibitors have also been demonstrated to show efficacy in preclinical models of anxiety and depression (Masood et al., Anxiolytic effects of phosphodiesterase-2 inhibitors associated with increased cGMP signaling, JPET 331(2):690-699, 2009; Masood et al., Reversal of Oxidative Stress-Induced Anxiety by Inhibition of Phosphodiesterase-2 in Mice, JPET 326(2):369-379, 2008; Reierson et al., Repeated antidepressant therapy increases cyclic GMP signaling in rat hippocampus, Neurosci. Lett., 466(3):149-53, 2009).
PDE2A protein expressed in the dorsal horn of the spinal cord and dorsal root ganglia enables PDE2A to modulate cyclic nucleotide levels in these regions during processing of neuropathic and inflammatory pain (Schmidtko et al., cGMP Produced by NO-Sensitive Guanylyl Cyclase Essentially Contributes to Inflammatory and Neuropathic Pain by Using Targets Different from cGMP-Dependent Protein Kinase I, The Journal of Neuroscience, 28(34):8568-8576, 2008).
In the periphery, the expression of PDE2A in endothelial cells has been demonstrated to play a critical role in regulation of endothelial barrier function. The expression levels of PDE2A in endothelial cells are increased in response to inflammatory cytokines such as TNF-alpha under conditions of sepsis and acute respiratory distress syndrome, and contribute to disruption of endothelial barrier function. Inhibition of PDE2A has been demonstrated to reverse permeability deficits in sepsis and enhance survival rates in animal models of sepsis and endotoxicosis (Seybold et al., Tumor necrosis factor-{alpha}-dependent expression of phosphodiesterase 2: role in endothelial hyperpermeability, Blood, 105:3569-3576, 2005; Kayhan et al., The adenosine deaminase inhibitor erythro-9-[2-hydroxyl-3-nonyl]-adenine decreases intestinal permeability and protects against experimental sepsis: a prospective, randomized laboratory investigation, Critical Care, 12(5):R125, 2008).
Certain imidazotriazines have been published as kinase inhibitors such as: International Patent Publication WO2011005909 entitled “Process for the preparation of substituted imidazo[5,1-f][1,2,4]triazine derivatives;” United States Patent Publication: US20090286768 entitled “Substituted imidazopyrazines and imidazotriazines as ACK1 inhibitors and their preparation;” International Patent Publication WO200911748 entitled “Preparation of mTOR inhibitor salt forms;” International Patent Publication: WO2009008992 entitled “Preparation of imidazo[1,5-a]pyrazin-8-amine for use in combination therapy of cancers and cancer metastasis;” United States Patent Publication US20080139582 entitled “Preparation of substituted pyrazolopyrimidinamines as inhibitors of Bruton's tyrosine kinase;” International Patent Publication: WO2007106503 entitled: Imidazo[1,5-a]pyrazin-8-amine in combined treatment with an EGFR kinase inhibitor and an agent that sensitizes tumor cells to the effects of EGFR kinase inhibitors;” International Patent Publication WO2007087395 enitled “Preparation of ethynyl- or vinyl-imidazopyrazines and imidazotriazines as mammalian target of rapamycin (mTOR) inhibitors for the treatment of cancer and other diseases;” United States Patent Publication US20070112005 entitled “Preparation of substituted imidazopyrazines and related compounds as mTOR inhibitors;” United States Patent Publication US20060019957 entitled “Preparation of imidazotriazines as protein kinase inhibitors;” and International Patent Publication WO2005097800 entitled “Preparation of 6,6-bicyclic ring substituted heterobicyclic protein kinase inhibitors”